Details of the Drug Combination

General Information of Drug Combination (ID: DC0H7KZ)

• Drug Combination Name: Imiquimod + Ingenol mebutate
• Indication: Keratosis, Actinic; Status: Phase 4 [1]
• Component Drugs:
  Imiquimod (DM1TMA3): Small molecular drug
  Ingenol mebutate (DMK1CZJ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Imiquimod

Disease Entry	ICD 11	Status	REF
Alopecia areata	ED70.2	Approved	[2]
Condyloma	1A95	Approved	[2]
Glioblastoma	2A00	Approved	[2]
Melanoma	2C30	Approved	[2]
Skin cancer	2C30-2C37	Approved	[3]

Imiquimod Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Toll-like receptor 7 (TLR7)	TTRJ1K4	TLR7_HUMAN	Agonist	[6]

Imiquimod Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]

Imiquimod Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Chemical Synthesis	[8]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Secretion	[9]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[10]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Secretion	[9]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[10]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Decreases Expression	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[12]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Increases Activity	[10]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[14]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Increases Secretion	[9]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Chemical Synthesis	[8]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Metabolism	[8]

Indication(s) of Ingenol mebutate

Disease Entry	ICD 11	Status	REF
Actinic keratosis	EK90.0	Approved	[4]
Melanoma	2C30	Phase 3	[5]

Ingenol mebutate Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[15]

Ingenol mebutate Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Decreases Expression	[16]

References

• [1] ClinicalTrials.gov (NCT02281682) IM Versus 5-FU Versus IMI Versus MAL-PDT in Treatment of Actinic Keratosis
• [2] Imiquimod FDA Label
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5003).
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7443).
• [5] ClinicalTrials.gov (NCT01546571) Study of a Melanoma Vaccine in Stage IIb, IIc, and III Melanoma Patients. U.S. National Institutes of Health.
• [6] Imiquimod enhances IFN-gamma production and effector function of T cells infiltrating human squamous cell carcinomas of the skin. J Invest Dermatol. 2009 Nov;129(11):2676-85.
• [7] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [8] The Toll-like receptor agonist imiquimod is metabolized by aryl hydrocarbon receptor-regulated cytochrome P450 enzymes in human keratinocytes and mouse liver. Arch Toxicol. 2019 Jul;93(7):1917-1926.
• [9] Cannabidiol selectively modulates interleukin (IL)-1 and IL-6 production in toll-like receptor activated human peripheral blood monocytes. Toxicology. 2021 Dec;464:153016. doi: 10.1016/j.tox.2021.153016. Epub 2021 Nov 2.
• [10] (9)-Tetrahydrocannabinol Suppresses Monocyte-Mediated Astrocyte Production of Monocyte Chemoattractant Protein 1 and Interleukin-6 in a Toll-Like Receptor 7-Stimulated Human Coculture. J Pharmacol Exp Ther. 2019 Oct;371(1):191-201. doi: 10.1124/jpet.119.260661. Epub 2019 Aug 5.
• [11] Imiquimod: a potential weapon against Dupuytren contracture. Med Hypotheses. 2006;66(5):991-2. doi: 10.1016/j.mehy.2005.09.052. Epub 2005 Dec 20.
• [12] Imiquimod induces apoptosis of human melanocytes. Arch Dermatol Res. 2010 May;302(4):301-6. doi: 10.1007/s00403-009-1012-0. Epub 2009 Dec 23.
• [13] Effect of toll-like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma. Liver Int. 2015 Mar;35(3):1063-76. doi: 10.1111/liv.12626. Epub 2014 Jul 30.
• [14] Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod. J Natl Cancer Inst. 2003 Aug 6;95(15):1138-49. doi: 10.1093/jnci/djg016.
• [15] The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. Cancer Res. 2010 Jun 1;70(11):4509-19.
• [16] Repurposing of ingenol mebutate for treating human colorectal cancer by targeting S100 calcium-binding protein A4 (S100A4). Toxicol Appl Pharmacol. 2022 Aug 15;449:116134. doi: 10.1016/j.taap.2022.116134. Epub 2022 Jun 18.